1-cyano-androstanes



3,954,809 l-CYANO-ANDROSTANES Albert Bowers and Howard J. Ringold,Mexico City, Mexico, assignors, by mesne assignments, to SyntexCorporation, a corporation of Panama No Drawing. Filed Feb. 5, 1960,Ser. No. 6,849 Claims priority, application Mexico Feb. 7, 1959 20Claims. (Cl. 260397.3)

The present invention relates to novel cyclopentanophenanthrenecompounds and process of preparing same.

More particularly the invention relates to novel l-cyano derivatives ofA -3-keto steroids of the androstane series which may or may not beoxygenated at C-ll.

The novel compounds of the present invention can be represented by thefollowing formula:

In the above formula Y represents hydrogen, keto and ,H-hydroxy; Arepresents keto,

in which R represents hydrogen or a hydrocarbon carboxylic acyl groupcontaining from 1 to 12 carbon atoms; R represents hydrogen or loweralkyl containing 1 to 5 carbon atoms and R represents hydrogen, methylor fluoro. The acyl group may be saturated or unsaturated, straightchain or branched chain aliphatic, cyclic or mixed cyclic aliphatic andmay be substituted as by hydroxy, acyloxy containing 1 to 12 carbonatoms, alkoxy containing 1 to 5 carbon atoms, or halogen such asfluorine, chlorine, bromine. Typical acyl groups of this type are theacetate, propionate, butyrate, hemisuccinate, enanthate, caproate,benzoate, trimethylacetate, phenoxyacetate, phenylpropionate,cyclopentylpropionate and ,8- chloropropionate.

The novel compounds of the present invention are valuable hormones ofthe androgenic type having a favorable anabolic-androgenic ratio andanti-estrogenic activity. The 17u-alkynyl derivatives particularlyexhibit progestational as well as anti-estrogenic activity.

The novel l-cyano compounds of the androstane series are prepared fromthe corresponding l-dehydro androstene compound. Since the cyanizationstep causes almost complete hydrolysis of esten'fied groups, it ispreferred that any hydroxy groups present in the starting material be inthe free form. The elements of hydrogen cyanide are added to thestarting l-dehydro compounds by refluxing the latter with an alkalimetal cyanide such as potassium cyanide or an alkaline earth metalcyanide in an alcoholic solvent, preferably ethanol or methanol. Thethus formed l-cyano compounds may then be esterified, if desired, byconventional methods. Thus by conventional reaction with thecorresponding acid anhydride or acyl chloride in pyridine solution atroom temperature there is prepared the corresponding C-17 esters ofthose products having a secondary alcohol group at C-17 and by reactionwith acid anhydride in the presence of an acid catalyst such asp-toluene-sulphonic acid, there is prepared the corresponding esters ofthose products having a tertiary alcohol group at C-17.

This invention is further illustrated but not limited by the followingexamples:

EXAMPLE 1 of pyridine and 1 cc. of acetic anhydride was kept at roomtemperature for 4 hours and poured into 'water; the precipitate wascollected by filtration, washed with water, dried and recrystallizedfrom acetone-hexane, thus aflording l-cyano-testosterone acetate.

EXAMPLE 2 .In accordance with the method of the previous example, 1 g.of 17a-methyl-l-dehydro-testosterone described in U.S. Patent 2,864,831,was converted into Hot-methyll-cyano-testosterone.

A mixture of 500 mg. of the above compound, 2.5 cc.

of acetic anhydride, 25 cc. of glacial acetic acid and 500 mg. ofp-toluenesulfonic acid was kept overnight at'room temperature, dilutedwith water and extracted several timeswith ethyl acetate. 5% aqueoussodium bicarbonate solution and water, dried over anhydrous sodiumsulfate and evaporated to dryness. Recrystallization of the residue fromacetone yielded methyl-l-cyano-testosterone 17-acetate.

EXAMPLE 3 By refluxing 1 g. of 17a-ethynyl-l dehydro-testosterone,described by Sondheimer et al. in JACS 77, 5673 (1955), with potassiumcyanide in ethanol, in accordance with the procedure described inExample 1, there was obtained 17a-ethynyl-1-cyano-testosterone.

' A mixture of 500 mg. of the above compound, 20 cc. of benzene, 1 g. ofcyclopentylpropionic acid anhydride and 200 mg. of p-toluenesulfonicacid was kept at room temperature for 48 hours, diluted with water,heated for half an hour on the steam bath, cooled and extracted withmethylene chloride. The extract was washed with aqueous sodiumbicarbonate solution and water, dried over anhydrous sodium sulfate andevaporated to dryness. By chromatography of the residue on neutralalumina there was obtained 17u-ethynyl-1-cyanotestosterone17-cyclopentylpropionate.

EXAMPLE 4 In accordance with the method described in Example 1, A-androstadien-3,17-dione was converted into l-cyano-A-androsten-3,17-dione.

EXAMPLE 5 hydride and kept overnight at room temperature. The

product was isolated as described in Example 1 for the acetylan'on ofl-cyano-testosterone, thus affording l-cyano-LI-keto-testosteronepropionate.

The starting material was obtained by the following method ofpreparation: a mixture of 5 g. of 11-keto-' testosterone, 2.15 g. ofselenium dioxide, 250 cc. of tbutanol and 0.6 cc. of pyridine wasrefluxed for 96 hours under an atmosphere of nitrogen and the mixturewas filtered through celite. The precipitate was Washed Patented Sept.18, 1962 The extract was washedwith' with 600 cc. of hot ethyl acetateand the combined filtrate and washings was concentrated to dryness undervacno, avoiding overheating. The residue was dissolved in 600 cc.of'acetone, mixed with 5 g. of charcoal, refluxed for half an hour,filtered and concentrated to a small vol ume. Upon cooling thecrystalline ll-keto-I-dehydrotestosterone was obtained. p A

Following the procedure of Example 1, the final prod ucts listed inTable I below, under III are obtained from the starting materials listedunder II, which in turn were obtained from the known compounds listedunder I by the method of preparation described in Example 5.

Table 1 Ex. No. I II III 6 l7a-ethyl-testosl-dehydro-l'laleyano-l'ia-ethylterone. ethyl-testes, testosterone.

- terone.

7 17apropy1-testos" 1-dehydr0-17w l-cyanodh-proterone.propyl-testospyl-testosterone.

1 terone.

8 171x-vinyl-test0s- 1-dehydro-17al-cyanodh-vinylterone.vinyhtestostestosterone.

- terone.

9 l7a-propin(llyl- I-dGhYdIO-I'Ya- 1-eyano-17a-pro testosterone J.propin(1)ylpin(1)yl-testos- Pharm. Phar testosterone. terone. maeol.1957 Vol.

10 17a-methy1-6al-dehydro-lh l-cyano lhfluoro-testosmethyl-6wmethylenterone. fluoro-testosfluoro-testosterone. terone.

V terone. terone.

12 l'ia-ethynyl-fiul-dehydro-l'ia-1-eyano-17amethyl-testosethynyl-fiarethynyl-fiaterone.methyl-testosmethyl-testosterone. terone.

13 fia-fluoro-testosl-dehydrdfial-cyanoea-fiuowterone.fluoro-testostestosterone.

- terone.

terone. methyl-testes yl-testosterone.

terone.

EXAMPLE 15 In accordancewith the method described in Example 1,1-dehydro-17m-propen-( 1)-y1-testosterone was converted into1-cyano-17a-propen-(1)-yl-testosterone. The starting material wasobtained from 17a-propin-(1)-yll-dehyd-ro-testosterone by partialhydrogenation of the triple bond by the method described by Sandoval etal. in JACS 77, 148 (1955).

EXAMPLE 16 In accordance with the procedure of Example 1, .1-dehydro-17a-butin-( 1)-yl-testosterone, obtained fromdehydroepiandrosterone with the aid of butine-(l) instead of acetyleneby the method described by Ruzicka et al. in Helv. Chim. Acta. 20, 1280(1937), followed by the dehydrogenation method described in Example 5,was converted into 1-cyano-17a-butyn-(1)-yl-testosterone.

EXAMPLE 17 In accordance with the method of Example 1, 1-de-'hydro-1LB-hydroxy-17a-methyl-testosterone, described in US. Patent2,864,832, was converted into 1-cyano-11,8-hydroxy-l7a-methyl-testosterone.

EXAMPLE 19* V By' applying the'rnethod of Example 1,l-dehydro-llketo-17a-ethinyl-testosterone, described by L. Velluz et al.in I. Am. Chem. Soc., 80, 2026, (1958), was converted into l-cyano-ll-ketol 7a-ethinyl-testosterone.

A mixture of 500 mg. of the above compound, 50 cc. of benzene, 1 cc. ofpropionic anhydride and 200 mg. of .p-toluenesulfonic acid was kept atroom temperature for 48 hours. It was then diluted with water andextracted with methylene chloride. The extract was washed with 5% sodiumcarbonate solution, dried over anhydrous sodium sulfate and evaporatedto dryness. By chromatography of the residue on neutral alumina therewas obtained l'ia-ethinyl-l-cyano-ll-keto-testosterone 17-propionate.

EXAMPLE 20 on g in which Y is selected from the group consisting of H onand keto; R is selected from the group consisting of hydrogen, methyland fiuoro; A is selected from the group consisting of keto,

CEO R wherein R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms and R isselected from the group consisting of hydrogen and lower alkyl.

. 3. IB-cyano-testosterone.

. 4. 1fl-cyano-6o-methy1-testosterone.

5. IB-cyano-ll-keto-testosterone.

6. 1B-cyano-A -androsten-3,11,17-trione.

7. 1fl-cyano-A -androsten-3,17-dione.

8. The hydrocarbon carboxylic acid esters of less than 12 carbon atomsof lB-cyano-testosterone.

9. lp-cyano-testosterone acetate.

10. 1,8-cyano-17u-lower alkyl-testosterone.

11. 1fi-cyano-17a-methyl-testosterone.

12. 1/8-cyano-6m-fluoro-17a-methyl-testosterone.

l3. lfl-cyano-llfi-hydroxy-17umethyl-testosterone.

14. The hydrocarbon carboxylic acid esters of less than 12 carbon atomsof 1,6-cyano-l7a-lower alkyl testosterone.

. 15. lfl-cyano-lh-lower alkenyl-testosterone. 16. lp-cyano-lh-loweralkynyl-testosterone.

17. lfl-cyano-17a-ethynyl-testosterone.

18. lfi-cyano-6u-methyl-17a-ethynyl-testosterone.

19. The hydrocarbon carboxylic acid ester of less than 12 carbon atomsof lfi-cyano-17a-lower alkynyl-testosterone. r

20. lfl-cyano-l7a-ethynyl-testosterone cyclopentylpropionate 7 Noreferences cited. 7

1. 1B-CYANO DERIVATIVES OF $4-3-KETO STEROIDS OF THE ANDROSTANE SERIES.